PROJECT SUMMARY/ABSTRACT The relationship between radiation therapy to the thorax and heart damage has been established through long-term studies of patients with breast cancer and Hodgkin lymphoma as cardiac disease became the primary non-cancer cause of death among such patients. Clinical treatments for both diseases have been adjusted to minimize radiation heart exposure by simple shielding and technical advances. For patients with locally advanced lung cancer, meaning that the mediastinal lymph nodes directly behind the heart are already involved with cancer, it is extremely difficult to avoid heart exposure during treatment owing to the physical location of the tumor. Yet little attention has been paid to this problem because of the assumption that radiation-induced cardiac damage is problematic only for patients who live longer than 5 years after their diagnosis. This excludes the vast majority of lung cancer patients, as their longevity with the current standard of care is estimated in the range of 18-24 months. This assumption that radiation causes only late- onset cardiac problems has been recently called into question. A recent phase III study suggested that poor survival rates of lung cancer patients may reflect the amount of heart tissue that is inadvertently exposed to radiation during treatment, which may cause premature death. We recently completed a randomized trial comparing protons and photons for lung cancer patients and found that proton therapy can significantly reduce unwanted radiation to the heart. However, we have not investigated if the reduction of radiation to the heart has reduced heart damage, nor if the reduction in heart exposure can translate to improved survival in patients with lung cancer. Damaged heart tissue releases cardiac troponin T (TnT), which is used widely in cardiology to diagnose and monitor heart damage after chemotherapy and radiation for breast cancer or lymphoma. Damaged heart tissue can also be visualized and quantified by PET scans. In this proposal, we will determine if reduced heart exposure to radiation by proton therapy can indeed reduce heart damage due to radiation in lung cancer patients. We will also determine if the reduced heart damage will improve the survival of these patients. Both of these goals will be analyzed by using a highly sensitive assay for cardiac TnT and the changes on the PET images from samples collected during the course of a completed randomized clinical trial. We will also investigate if certain heart structures are more sensitive to radiation by leveraging detailed dosimetry of implemented treatment plans. While this proposal carries risk that no cardiac benefit will be found after proton radiation, it also carries the potential of significant clinical impact as it could lead to practice-changing findings.